For prophylaxis, it is essential that vaccines cause minimal morbidity. Live vaccines, including attenuated viruses or viral vectors, have the potential to cause disease, particularly in immuno-compromised individuals. For this reason, the ideal vaccines for prophylaxis contain nonliving components, termed subunit vaccines. One limitation of subunit immunizations is that they generally induce weaker and less long-lasting immunity than live vaccines, therein limiting their efficacy. Moreover, subunit vaccines do not effectively stimulate cytotoxic T lymphocytes (CTLs), cells which mediate one of the major immune responses that protects against viral infections. CTLs kill host cells that are infected by a virus and thereby eliminate the production and/or reservoir of virus. CTLs are critical components in the defense against several viruses including influenza, Pox and LCMV (4-6), as well as some parasites and bacteria. Given the important role of CTLs in host defense, there is a pressing need to develop vaccines that stimulate this arm of the immune system.
It has been known since the 1920's that immunization with a foreign protein by itself was often ineffective in stimulating immunity.2 To generate immune responses the antigen needed to be admixed with other molecules that helped generate immunity. These molecules were termed adjuvants, from the Latin word “adjuvare”, which means to help. Because many of the adjuvant molecules were derived from bacteria, this has been described as the “immunologist's dirty little secret”.3 Why adjuvants are required and how they work to promote immunity has become apparent only in recent years.
Currently there are only two adjuvants approved for use in man. One of these, Alum, functions only weakly and appears to induce preferentially TH2 immunity, a type of immunity which is inappropriate for many pathogens. While other adjuvants have been developed, approval for use in man has been elusive due to unacceptable side effects including inflammation and carcinogenicity. Accordingly, there is the need to develop new and better adjuvants.
Currently, the kinds of adjuvants that are available are formulations that create a depot of antigen and/or contain microbial components that help stimulate responses. There is some evidence that mammalian cells also produce their own adjuvants (termed “endogenous adjuvants” or “danger signals”), molecules that are released when the cells are injured and that help stimulate immune responses. However, to date, these endogenous adjuvants have not been isolated in a form that is useful for vaccines and their molecular identity is unknown. Therefore, elucidation of the molecular identity of these endogenous adjuvant molecule(s) is clearly needed as they could be highly useful as a novel class of adjuvants for vaccines.